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Small Fiber Neuropathy diagnosis, a french team study, 2020

pattismith

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Front. Neurol., 05 May 2020 | https://doi.org/10.3389/fneur.2020.00342

Which Method for Diagnosing Small Fiber Neuropathy?

Vincent Fabry
1,2*,
Angélique Gerdelat3,
Blandine Acket1,
Pascal Cintas1,
Vanessa Rousseau4,
Emmanuelle Uro-Coste2,5,6,
Solène M. Evrard2,5,6 and
Anne Pavy-Le Traon
1,2,7

Introduction: Small fiber neuropathies (SFN) induce pain and/or autonomic symptoms.

The diagnosis of SFN poses a challenge because the role of skin biopsy as a reference method and of each neurophysiological test remain to be discussed.

This study compares six methods evaluating small sensory and autonomic nerve fibers:

- skin biopsy,
-Quantitative Sensory Testing (QST), Thermotest
-quantitative sweat measurement system (Q-Sweat),
-Laser Evoked Potentials (LEP),
- Electrochemical Skin Conductance (ESC) measurement Sudoscan
-Autonomic CardioVascular Tests (ACVT).

Methods: This is a single center, retrospective study including patients tested for symptoms compatible with SFN between 2013 and 2016 using the afore-mentioned tests.
Patients were ultimately classified according to the results and clinical features as “definite SFN,” “possible SFN” or “no SFN.”
The sensitivity (Se) and specificity (Sp) of each test were calculated based on the final diagnosis and the best diagnostic strategy was then evaluated.

Results: Two hundred and forty-five patients were enrolled (164 females (66.9%), age: 50.4 ± 15 years).

The results are as follows:

-skin biopsy: Se = 58%, Sp = 91%;
-QST: Se = 72%, Sp = 39%;
-Q-Sweat: Se = 53%, Sp = 69%;
-LEP: Se = 66%, Sp = 89%;
-ESC: Se = 60%, Sp = 89%;
-Cardiovascular tests: Se = 15%, Sp = 99%.


The combination of skin biopsy, LEP, QST and ESC has a Se of 90% and a Sp of 87%.

Conclusion: Our study outlines the benefits of combining skin biopsy, ESC, LEP and QST in the diagnosis of SFN.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214721/pdf/fneur-11-00342.pdf
 
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pattismith

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it's interesting to notice that those tests have different sensitivity and specificity,
with QST having the best sensitivity and Cardiov test having the best specificity.
It means that Skin Biopsy, often presented as the SFN gold standard diagnosis test,
Skin Biopsy alone doesn't have the best sensitivity nor the best specificity!

It's also interesting to notice that these tests doesn't explore the same small fibers:

1593871245759.png
 

wigglethemouse

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It's also interesting to notice that these tests doesn't explore the same small fibers:
That's a key point I think.

I wonder why the skin biopsy was just one location. When I had mine it was two locations
A skin biopsy was performed with a 3-mm punch in a single site in the distal leg and processed as described by Lauria et al. (2, 3) in order to determine the IENFD. IENFD values were compared to normative values published by Lauria et al. (2) the biopsy was considered abnormal if the IEFND was lower than anticipated for age and gender (<5th percentile).
I would have liked to have seen some discussion on threshold levels used as this will effect sensitivity and specificity. For biopsy <5% of population is normally used and this is kind of arbitrary.

This was interesting. Is it functional differences or as @pattismith said - the tests measure different nerve fibers
Therefore, it is uncertain whether skin biopsy can be considered as a reference method for the diagnosis of SFN. A significant proportion of the SFNs could be related to functional impairment of small fibers, detectable by functional explorations, but without fiber destruction as evidenced in biopsy.
I would have liked to have seen a comparison between tests for those whose skin biopsy IENFD was at the very low end of the spectrum - do those people automatically fail all the other tests or is it more nuanced.........
 

pattismith

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That's a key point I think.

I wonder why the skin biopsy was just one location. When I had mine it was two locations


I would have liked to have seen some discussion on threshold levels used as this will effect sensitivity and specificity. For biopsy <5% of population is normally used and this is kind of arbitrary.

This was interesting. Is it functional differences or as @pattismith said - the tests measure different nerve fibers


I would have liked to have seen a comparison between tests for those whose skin biopsy IENFD was at the very low end of the spectrum - do those people automatically fail all the other tests or is it more nuanced.........
SFN diagnosis is not yet standardized, and skin biopsy has it's own limitation. The team pointed also the staining technique that can alter the interpretation.

They based their definite diagnosis on testing and conclude that "it is uncertain wether a skin biopsy can be considered as a reference method for the diagnosis of SFN. A significant proportion of the SFNs could be related to functional impairment of small fibers, detectable by functional explorations, but without fiber destruction as evidenced in biopsy"

I do agree with this conclusion, and I think it is particularly relevant for genetic SFN. Unfortunately they failed to diagnose genetic channelopathies causes in their study, because "search for channelopathy was not systematically part of the SFN diagnosis at that time"

It's sad that they were so long to publish (patients tested between 2013 and 2016)!
Medecine deperately need good tools for SFN diagnosis...

@pattismith s4me has a thread on a study of Laser Evoked Potentials in CFS and chronic whiplash vs healthy controls and found no group differences.. LEP is one of the screening tools used in this study.
would you give me the link to the study here please, I'm very interested to read it.

Not sure of LEP is the best tool for CFS anyway: It only adress Adelta sensory fibers.

It's interesting to notice that ESC seems to be the best autonomic test in regard to SFN diagnosis
 

pattismith

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I also noticed that there was not healthy control.
"245 patients referred to the laboratory with suspected SFN were enrolled in the study.
....inclusion criteria:
(1) sensory and/or autonomic symptoms consistent with SFN;
(2) normal nerve conduction (normal ulnar, median, sural, superficial peroneal sensory responses and ulnar, median, tibial, peroneal motor responses with F-waves) according to our laboratory normative values."

In the result table, they found
- 102 Definite SFN,
- 53 Possible SFN
- 90 No SFN


So this methode may not be as sensible as they say, because 53 patients doesn't get a definitive diagnosis and may be real SFN.

The other problem I see in this method of SFN diagnosis is it means to diagnose mostly skin SFN.
(Only the cardiovascular test target other than skin small nerve fibers....)

According to Disautonomia international, "Approximately 50% of POTS patients have a small fiber neuropathy that impacts their sudomotor nerves ", could it be that some others may have SFN that target vessels but not the skin?

It's interesting to notice the mean Systolic Blood Pressure variation in upright posture/mmHg in this cohort:

Definite SFN -3.75
Possible SFN -5.38
No SFN -1.89

and the mean Diastolic BP variation in upright posture:

Definite SFN -4.44
Possible SFN -1.47
No SFN -3.15

this "possible SFN" group seems to have different BP variations to upright posture than the two other patient groups.... I think there is something not fully elucidated here...
 

wigglethemouse

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would you give me the link to the study here please, I'm very interested to read it.
Here is the study.
Processing of Laser-Evoked Potentials in Patients with Chronic Whiplash-Associated Disorders, Chronic Fatigue Syndrome, and Healthy Controls: A Case–Control Study
Paywall, https://academic.oup.com/painmedicine/article-abstract/doi/10.1093/pm/pnaa068/5820105
Sci hub, https://sci-hub.tw/10.1093/pm/pnaa068
Abstract
Objective

Laser-evoked potentials (LEPs) are among the reliable neurophysiological tools to investigate patients with neuropathic pain, as they can provide an objective account of the functional status of thermo-nociceptive pathways. The goal of this study was to explore the functioning of the nociceptive afferent pathways by examining LEPs in patients with chronic whiplash-associated disorders (cWAD), patients with chronic fatigue syndrome (CFS), and healthy controls (HCs).

Design
Case–control study.

Setting
A single medical center in Belgium.

Subjects
The LEPs of 21 patients with cWAD, 19 patients with CFS, and 18 HCs were analyzed in this study.

Methods
All participants received brief nociceptive CO2 laser stimuli applied to the dorsum of the left hand and left foot while brain activity was recorded with a 32-channel electroencephalogram (EEG). LEP signals and transient power modulations were compared between patient groups and HCs.

Results
No between-group differences were found for stimulus intensity, which was supraliminal for Ad fibers. The amplitudes and latencies of LEP wave components N1, N2, and P2 in patients with cWAD and CFS were statistically similar to those of HCs. There were no significant differences between the time–frequency maps of EEG oscillation amplitude between HCs and both patient populations.
Conclusions

EEG responses of heat-sensitive Ad fibers in patients with cWAD and CFS revealed no significant differences from the responses of HCs. These findings thus do not support a state of generalized central nervous system hyperexcitability in those patients.
 

pattismith

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Here is the study.
Processing of Laser-Evoked Potentials in Patients with Chronic Whiplash-Associated Disorders, Chronic Fatigue Syndrome, and Healthy Controls: A Case–Control Study
Paywall, https://academic.oup.com/painmedicine/article-abstract/doi/10.1093/pm/pnaa068/5820105
Sci hub, https://sci-hub.tw/10.1093/pm/pnaa068
thank you, it's interesting to note that another team found in a 2019 study;

Fibromyalgia syndrome—A laser‐evoked potentials study unsupportive of small nerve fibre involvement


"None of the FMS patients showed signs of loss of function of the nociceptive responses evoked by A δ‐nociceptor activation, compared to healthy controls.
6.5% of the FMS patients had N2‐P2 peak‐to‐peak amplitudes above the upper limit of the 99%‐confidence interval. ...

The characteristic signs of a damaged thermo‐nociceptive system as revealed by LEPs were absent in this large cohort of FMS patients.

The present research does not support the hypothesis that small fiber neuropathy is a significant contributor to the pathophysiology of FMS."


The conclusion is weird, it just means that Adelta fibers are probably not involved in Fibro SFN, exactely the same as for ME/CFS.

SFN is found in 40 to 50 % of Fibro and ME/CFS patients, and probably mostly from Autonomic C fibers dysfunction, then spreading over time to sensory C fibers...

https://onlinelibrary.wiley.com/doi/full/10.1002/ejp.1501
 

pattismith

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So there isn't yet any standardized diagnosis nor consensus for SFN...

This paper (april 2020) was written by docs heavily paid by drug laboratories.....
it's interesting that the criteria they propose does not include autonomic testing, nor autonomic symptoms, and the only positive objective test include is the skin biopsy:

" Requirements for an iDSP diagnosis include:

-one of the following symptoms
(1) spontaneous or constant pain,
(2) allodynia,
(3) a non-painful sensory symptom;

-one of the following signs:
(1) abnormal sensory perception (i.e., pinprick, light touch, vibration, or position sense),
(2) allodynia,
(3) hyperalgesia;

-abnormalities in sensory nerve conduction studies or distal intra-epidermal nerve fiber density;
-and absence of specific causes of DSP.

Diagnostic criteria for iSFN are similar, except absence of abnormalities in large fiber clinical signs (e.g., vibration perception) and normal sensory nerve conduction studies are required.

Diagnostic Criteria for Idiopathic Distal Sensory Polyneuropathy and Idiopathic Small Fiber Polyneuropathy